Highly enantioselective Michael addition of malonates to β,γ-unsaturated α-ketoesters catalyzed by chiral N,N′-dioxide-Yttrium(iii) complexes with convenient procedure

Article abstract of DOI:10.1039/c002208j

Highly enantioselective Michael addition of malonates to β,γ-unsaturated α-ketoesters has been promoted by chiral N,N′-dioxide-Yttrium(iii) complexes, providing the corresponding products in excellent yields with 94-99% ee values.

Full text of DOI:10.1039/c002208j

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Highly enantioselective Michael addition of malonates to b,c-unsaturated
a-ketoesters catalyzed by chiral N,N0-dioxide-Yttrium(III) complexes with
convenient procedurew
Lin Zhou, Lili Lin, Wentao Wang, Jie Ji, Xiaohua Liu* and Xiaoming Feng*
Received 2nd February 2010, Accepted 11th March 2010
First published as an Advance Article on the web 8th April 2010
DOI: 10.1039/c002208j
Highly enantioselective Michael addition of malonates to
b,c-unsaturated a-ketoesters has been promoted by chiral
N,N0-dioxide-Yttrium(III) complexes, providing the corresponding
products in excellent yields with 94–99% ee values.
coordinated with Lewis acid Sc(OTf)3 to catalyze the asymmetric
Michael addition of dimethyl malonate 1a to b,g-unsaturated
a-ketoester 2a in CH2Cl2 at 0 1C, however, only a trace of
product was obtained. Several other Lewis acids, such as
La(OTf)3, Sm(OTf)3, Yb(OTf)3 and Y(OTf)3 were then investi-
gated. It was found that Y(OTf)3 was superior to all the other
metals, producing 3a in 79% yield with 66% ee (Table 1,
entries 2–5). To further improve the enantioselectivity, the
steric and electronic effects of the ligand were examined
(Table 1, entries 6–10). As shown in Table 1, ligands with
a bulkier group at the ortho position of aniline, such as
isopropyl in L6, could obtain the Michael adduct with higher
enantioselectivity (up to 99% ee; Table 1, entry 10 vs. entries
6–9). As for the chiral backbone moiety, the N,N0-dioxide
derived from (S)-pipecolic acid exhibited its superiority in
enantioselectivity toward this reaction compared with the ones
derived from L-proline and (S)-ramipril (Table 1, entry 10 vs.
entries 11 and 12).
The catalytic asymmetric Michael addition, affording syn-
thetically useful building blocks in organic synthesis, is one of
the most powerful methods for construction of stereocenters.1,2
Comparing with numerous Michael addition of a,b-unsaturated
ketones,3–5 the reactions which used b,g-unsaturated a-ketoesters
as Michael acceptors were very limited.6 To the best of our
knowledge, the asymmetric Michael addition of malonates to
b,g-unsaturated a-ketoesters has not been achieved. So, it is
highly desirable to develop an enantioselective version due to
the fact that the adducts have the potential for functionalizing
to the corresponding amino acid esters7 or a-hydroxy acid
esters.
Inspired by our previous studies,8 we studied the asymmetric
Michael addition of malonates to b,g-unsaturated a-ketoesters
catalyzed by a metal complex, it was found that N,N0-dioxide-
Y(OTf)3 complex could highly catalyze the reaction with a
convenient procedure, affording the desired products with up
to 99% yield and 99% ee. This catalytic reaction is remarkable
as no exclusion of air and humidity is required, the liquid
substrates can be used as solvent, and there are very con-
venient operation and mild reaction conditions.
Table 1 Optimization of the reaction conditions
Entrya Ligand Metal
x (mol%) Yieldb (%) Eec (%)
1
2
3
4
5
6
7
8
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L7
L8
L6
L6
L6
L6
—
Sc(OTf)3
La(OTf)3
Sm(OTf)3
Yb(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
Y(OTf)3
—
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
2
Trace
56
50
58
79
79
71
74
73
76
76
74
80
83
91
Trace
Trace
91
—
24
34
60
66
66
58
94
90
99
96
96
98
98
96
—
—
98
In our preliminary investigation, the chiral N,N0-dioxide
ligand L1 (Fig. 1) derived from (S)-pipecolic acid was
9
10
11
12
13d
14de
15f , g
16f , g
17f , g
18f , g
Y(OTf)3
Y(OTf)3
L6
Fig. 1 Chiral ligands used in the study.
a
Unless otherwise noted, the reactions were performed with 2a
(0.10 mmol), N,N0-dioxide (x mol%), metal (x mol%) in CH2Cl2
(0.2 mL) at 25 oC for 0.5 h, then malonates (0.12 mmol) were added at
Key Laboratory of Green Chemistry & Technology,
Ministry of Education, College of Chemistry, Sichuan University,
Chengdu 610064, P. R. China. E-mail: xmfeng@scu.edu.cn;
Fax: +86 28 85418249; Tel: +86 28 85418249
w Electronic supplementary information (ESI) available: Experimental
details. See DOI: 10.1039/c002208j
b
0 1C. The reaction mixture was stirred at 0 1C for 48 h. Isolated
yield. Determined by HPLC analysis (Chiralcel AD-H). The
c
d
e
solvent was 0.1 mL. Reaction was performed for 96 h. Liquid
f
g
substrates as solvent. Reaction was performed for 4 h.
ꢀc
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To improve the yield, increasing the reaction concentration
and prolonging the reaction time were tried. However, the results
were not satisfactory (Table 1, entries 13–14). Interestingly,
the yield was improved to 91% and the ee was basically
maintained when the reaction was carried out with excessive
dimethyl malonate as solvent (96% ee; Table 1, entry 15), and
also the reaction time was reduced to 4 h rather than 96 h in
CH2Cl2. Moreover, the experimental procedure became
very simple since neither ligand nor metal could promote the
reaction (Table 1, entries 16–17). Preparing the catalyst before-
hand and exclusion of air and humidity were unnecessary. The
specific operation was as follow: the solid substrate, ligand and
metal were weighed in a dry reaction tube followed by addition
of dimethyl malonate at 0 1C, then the reaction mixture was
stirred at 0 1C for 4 h. To our delight, reducing the catalyst
loading to 2 mol% also gave the desired product with up to
91% yield and 98% ee (Table 1, entry 18).
and ee value (Table 2, entry 18). Moreover, a heteroaromatic
substrate delivered the Michael adduct in excellent yield and
enantioselectivity (Table 2, entry 19).
Though dimethyl malonate was used in great excess in these
milligram scale reactions (Table 2), the ratio of dimethyl
malonate to b,g-unsaturated a-ketoesters could be reduced to
2.5 : 1 or 5 : 1 when the reactions were amplified to gram scales.
As shown in Scheme 1, the reactions proceeded smoothly in
high yields with excellent ee values on gram scales in the
presence of only 1–2 mol% L6-Y(OTf)3 complex, which
showed the synthetic utility of the catalytic system.
On account of the synthetic potential of this Michael
addition, the product 3a was simply converted into an usefully
functionalised a-hydroxy acid ester (Scheme 2) using NaBH4
as the reductive, 99% yield, 97% ee (major), 99% ee (minor)
and 78 : 22 dr were obtained.
In conclusion, we have demonstrated that the asymmetric
Michael addition of malonates to b,g-unsaturated a-ketoesters
could be carried out without extra solvent. The reaction was
promoted by a highly efficient N,N0-dioxide L6-Yttrium(III)
complex with low catalyst loadings (2–5 mol%), affording
the corresponding 4-oxo-2-arylbutane-1,1,4-tricarboxylate
Under the optimized conditions (Table 1, entry 18) with the
convenient procedure, the substrate scope for this asymmetric
Michael addition of dimethyl malonate to b,g-unsaturated
a-ketoesters was tested and the results were summarized in
Table 2. No matter whether R2 was methyl or ethyl, the
substrates 2a–b gave excellent yields (91%, 97%) and ee values
(98%, 97%; Table 2 entries 1–2). The substrates with electron-
withdrawing or donating groups at any position of the aromatic
ring were well tolerated in terms of yields and enantio-
selectivities, and up to 99% yield and 99% ee were obtained
(Table 2, entries 3–16). A fused ring b,g-unsaturated a-ketoester
3q was also a suitable substrate for the reaction, giving the
corresponding product with up to 98% ee (Table 2, entry 17).
The substrate with cinnamyl group also gave an excellent yield
Scheme 1 Asymmetric conjugate addition of dimethyl malonate to
b,g-unsaturated a-ketoesters on a gram scale.
Table 2 Substrate scope for asymmetric Michael addition
Entrya
R1
Product
1ab/mL
x (mol%)
t/h
Yieldc (%)
Eed (%)
1
2
3
4
5
6
7
8
Ph
Ph
4-FC6H4
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
0.1
0.2
0.2
0.3
0.2
0.2
0.2
0.3
1.0
0.5
0.5
0.2
0.2
0.5
0.3
2
5
5
5
5
2
2
5
5
5
2
2
5
5
5
4
12
5
5
8
4
20
5
24
24
24
24
8
91
97
99
97
80
99
95
85
82
94
83
99
87
99
89
98
97
98
98
95
98
99
97
97
95
99
96
96
95
94
4-ClC6H4
2-ClC6H4
2,4-Cl2C6H3
4-BrC6H4
3-BrC6H4
4-NO2 C6H4
3-NO2 C6H4
4-CNC6H4
4-CH3C6H4
3-CH3C6H4
4-PhC6H4
4-CH3OC6H4
9
10
11
12
13e
14
15
60
72
16
3p
0.5
5
72
92
94
17
18
19
2-Naphthyl
–CHQCHPh
2-Thienyl
3q
3r
3s
0.2
0.5
0.2
2
5
5
24
24
24
95
86
95
98
98
97
a
Unless otherwise noted, the reactions were performed with 2 (0.10 mmol), N,N0-dioxide (x mol%), metal (x mol%) in a dry reaction tube, then
b
c
dimethyl malonate 1a was added at 0 1C. The reaction mixture was stirred at 0 1C for the indicated time. The amount of 1a. Isolated
yield. Determined by HPLC analysis (Chiralcel AD-H). Reaction was performed at 25 1C.
d
e
ꢀc
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Scheme 2 The conversion of product 3a into an usefully functiona-
lised a-hydroxy acid ester.
compounds in excellent yields and ee values. Atmospheric
oxygen and water did not affect the outcome and the procedure
was very simple. The reaction could be amplified to gram
scales with good yields and ee values in the presence of only
1–2 mol% catalyst loading and the adducts could be converted
into the corresponding useful a-hydroxy acid esters, which
showed the potential value of the catalytic system for practical
synthesis. Further applications of the current catalyst system
to other reactions are underway.
We appreciate the National Natural Science Foundation of
China (Nos. 20732003 and 20872097), PCSIRT (No. IRT0846)
and National Basic Research Program of China (973 Program)
(No. 2010CB833300) for financial support. We also thank
Sichuan University Analytical & Testing Center for NMR
analysis.
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ꢀc
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Chem. Commun., 2010, 46, 3601–3603 | 3603